Poor performance of laboratories assaying newly developed antiretroviral agents: Results for darunavir, etravirine, and raltegravir from the international quality control program for therapeutic drug monitoring of antiretroviral drugs in human plasma/serum

BACKGROUND:: The International Interlaboratory Quality Control Program for Therapeutic Drug Monitoring of Antiretroviral Drugs in Human Plasma/Serum was initiated in 1999. We have previously published our experience during the first 10 years of the Program. Since 2010, 3 newly developed antiretroviral agents have been added to the Program: darunavir, etravirine, and raltegravir. The objective of this analysis is to describe the performance of participating laboratories measuring these newer agents in 2011-2012. MATERIALS AND METHODS:: Each year, laboratories received 2 blind samples of human plasma/serum spiked with a low (<1.0 mg/L), medium (1.0-5.0 mg/L), or high (>5.0 mg/L) concentration of these drugs. Laboratory results were standardized to percentages with reference to the nominal (true) concentration. Any result that deviated more than 20% of the nominal values was defined as inaccurate. RESULTS:: The numbers of laboratories that participated by the end of 2012 were 44 for darunavir, 28 for etravirine, and 30 for raltegravir. A total of 357 results were evaluable for analysis. Of these, 64 (17.9%) results were reported with >20% deviation, so "inaccurate" (7.6% too low, 10.4% too high). The proportion of inaccurate results in 2011 was 21.3% for darunavir, 31.0% for etravirine, and 26.3% for raltegravir; in 2012, these figures improved to 8.1%, 23.2%, and 8.3% for darunavir, etravirine, and raltegravir, respectively. Taking darunavir as the reference, performance for etravirine was significantly lower [odds ratio = 0.462, 95% confidence interval: 0.246-0.866, P = 0.016] and performance for raltegravir was not significantly different. Low concentrations were significantly more frequently reported as inaccurate than medium or high concentrations: 28.6% versus 10.6% versus 8.8%, respectively (P < 0.001). Laboratories that used Liquid Chromatography with tandem Mass Spectrometry did not perform better than those using High Performance Liquid Chromatography/Ultrarapid Performance Liquid Chromatography: 41 inaccurate results in 200 samples (20.5%) versus 23 in 157 samples (14.6%, P = 0.154). Multiple logistic regression revealed that the concentration range was the only significant predictor of inaccurate results. The lower range of concentrations performed worse than medium or high concentrations (P < 0.001). CONCLUSIONS:: Laboratories continue to have problems with adequately measuring low plasma concentrations of antiretroviral agents. This is particularly a problem for some of the newer antiretroviral agents with plasma concentrations in the <1.0 mg/L range, such as etravirine and raltegravir.